The field of this invention is modulation of mammalian endocrine systems.
The mammalian endocrine system is critical to mammalian cell-cell communication. In the endocrine system, hormones are secreted by endocrine glands into the circulatory system and adsorbed onto specific receptors, usually located distal to the site of secretion. The endocrine system is used by mammals to orchestrate a variety of different physiological processes, including metabolism, growth and maturation, circadian cycles and the like.
An important member of the endocrine system is the hypothalamic-pituitary axis. In general, this member of the endocrine system has two components: 1) a magnocellular (large cell) system which releases the hormones oxytocin and vasopressin (arginine vasopressin, AVP) directly into the blood stream from axon terminals located in the posterior pituitary and 2) a parvocellular (small cell) system that secretes small peptides called releasing factors which enter fenestrated capillaries, descend through the hypophyseal portal veins, and then diffuse through additional fenestrated capillaries to individual cells of the anterior pituitary. Principal neuropeptides secreted by the hypothalamus include growth hormone releasing hormone (GHRH), growth hormone release-inhibiting hormone (somatostatin), prolactin release inhibitory factor (dopamine), gonadotropin-releasing hormone (GnRH), corticotropin-releasing hormone (CRH), and thyrotropin-releasing hormone (TRH). Hormones released by the pituitary in response to hypothalamus neuropeptide influence include growth hormone (GH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH, corticotropin) and thyrotropin (thyroid stimulating hormone, TSH).
The magnocellular and parvocellular secretory regions of the hypothalamus receive strong inputs from a variety of regions including other segments of the hypothalamus, diverse areas of the brain stem, and from forebrain (telencephalic) structures. See FIG. 1. Prominent in the last group are projections from the limbic system including the central and medial divisions of the amygdala and the closely related bed nucleus of the stria terminals.
Abnormalities in endocrine or hormonal systems, e.g. hypo- or hypersecretion of one or more particular hormones, can have a profound affect on the ability of a mammal to function. For example, hypersecretion of pituitary hormones can result in a number of different diseased states, including: Cushing""s syndrome (ACTH), acromegaly and gigantism (GH), and the like. Hyposecretion of pituitary hormones is also implicated in a number of diseased states, including dwarfism (GH), Sheehan""s syndrome (panhypopituitarism), and the like.
Recently, age dependent dysfunction of hormonal systems has been postulated to be associated with the mammalian aging process. For example, GH blood levels in the elderly are lower than GH blood levels in younger populations, where lower GH blood levels have been theorized to be associated with symptoms of the aging process, such as decreases in lean body mass, muscle and bone.
Current methods of treating diseases associated with endocrine system dysfunction involving the hyposecretion of one or more particular hormones have centered on direct hormonal replacement, e.g. synthetic or recombinant growth hormone for GH deficient youths. While such approaches can be successful, hormone replacement therapy can be associated with a number of different disadvantages, such as risk of pathogen transmission, delivery, over compensation of replacement hormone, and the like.
As such, there continues to be an interest in the development of new methods of treating diseases characterized by endocrine system dysfunction. Of particular interest is the identification of small molecules which have a modulatory effect in the amount of endogenous hormone production, and methods of using such molecules in the regulation of hormonal circulatory levels.
References describing the presence and distribution of AMPA type glutamate receptors in the hypothalamus include: Aubry et al., (1996) xe2x80x9cExpression of ionotropic receptor subunit mRNAs by paraventricular corticotropin-releasing factor (CRF) neurons,xe2x80x9d Neurosci. Lett. 205:95-98; Van den Pool et al. (1994) xe2x80x9cIonotropic glutamate receptor gene expression in the hypothalamus: Localization of AMPA, kainate and NMDA receptor mRNA with in situ hybridization,xe2x80x9d J. Comp. Neurology 343:428-444; Brann (1995) xe2x80x9cGlutamate: a major excitatory transmitter in neuroendocrine regulation. Neuroendocrinology 61:213-225; Ginsberg et al. (1995) xe2x80x9cThe AMPA glutamate receptor GluR3 is enriched in oxytocinergic magnocellular neurons and is localized at synapses,xe2x80x9d Neuroscience 65:564-575.
References describing the effects of AMPA receptor agonists on the excitation of hypothalamic neurons and on the release of releasing factors include: Nissen et al. (1995), xe2x80x9cRegulation of spontaneous phasic firing of rat supraoptic vasopressin neurons in vivo by glutamate receptors,xe2x80x9d J. Physiol. 484:415-424; Donoso et al. (1990) xe2x80x9cGlutamate receptors of the non-NMDA types mediate the increase in Luteinizing Hormone-Releasing Hormone release by excitatory amino acids,xe2x80x9d Endocrinology 126:414-420; Lopez et al. (1992) xe2x80x9cEndogenous excitatory amino acids and glutamate receptor subtypes involved in the control of hypothalamic luteinizing hormone-releasing hormone secretion,xe2x80x9d Endocrinology 130:1986-1992; Parker and Crowley (1993) xe2x80x9cStimulation of oxytocin release in the lactating rat by central excitatory amino acid mechanisms: evidence for specific involvement of AMPA sensitive glutamate receptors,xe2x80x9d Endocrinology 133:2847-2854; Brann et al. (1993) xe2x80x9cRole of non-NMDA receptor neurotransmission in steroid and preovulatory gonadotropin surge expression in the female rat,xe2x80x9d Mol. Cell. Neurosci. 4:292-297; Ping et al. (1994) xe2x80x9cA physiological role for N-methyl-D-aspartic acid and non-N-methyl-D-aspartic acid receptors in pulsatile gonadotropin secretion in the adult female rat.xe2x80x9d Endocrinology 135:113-118.
References studying the influence of glutamate receptor agonists on gene expression of hypothalamic factors include: Gore and Roberts (1994) xe2x80x9cRegulation of GnRH gene expression by the excitatory amino acids kainic acid and NMDA in the male rat,xe2x80x9d Endocrinology 134:2026-2031. References describing age associated changes in the production of pituitary hormones include: Crew et al. (1987) xe2x80x9cAge-related decrease of growth hormone production and prolactin gene expression in the mouse pituitary,xe2x80x9d Endocrinology 121:1251-1255; Martinoli et al. (1991) xe2x80x9cGrowth hormone and somatostatin gene expression in adult and aging rats as measured by quantitative in situ hybridization,xe2x80x9d Neuroendocrinology 57:607-615.
Methods for modulating mammalian endocrine systems are provided. In the subject methods, allosteric modulators of AMPA receptors of the hypothalamus, e.g. agents belonging to the xe2x80x9campakinexe2x80x9d family of compounds, are administered to the host. The subject methods find use in a variety of different applications where modulation of the endocrine system of a mammal is desired, such as in the treatment of diseases associated with hormonal system dysfunction, particularly with abnormally decreased circulatory levels of a hormone, e.g. growth hormone, resulting from down regulation in endogenous hormonal production.
It is an object of the invention to treat hormonal imbalances. Another object of the invention is to show the effects of aging related to decreases in hormonal levels which normally occur with aging.
An advantage of the invention is that a host""s endogenous hormones are used.
A feature of the invention is that formulations with specific positive modulators of AMPA type glutamate receptors are employed.
These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the subject invention, as more fully described below.
FIG. 1 provides a schematic diagram showing the various diverse influences on the magnocellular and parvocellular secretory regions of the hypothalamus.
FIG. 2 provides a graphical representation of the effects of prolonged administration of GR87 on serum GH levels.
FIG. 3 provides a graphical representation of the effects of GR87 exposure on the secretion of GHRH by hypothalamic cells in culture.